Our overall goal is to develop effective, clinically applicable, approaches to restore upper limb function (reach- and-grasp) after chronic contusive cervical spinal cord injury (cSCI). Impairments in upper limb function significantly reduce the quality of life for people with cSCI. Reach-and-grasp actions in animals and humans are largely controlled by the corticospinal tract (CST). We argue that promoting plasticity within the CST may support the recovery of upper limb function after cSCI. Repetitive exposure to acute intermittent hypoxia (rAIH) combined with motor training is a safe, minimally invasive, treatment that elicits neuroplasticity resulting in improved recovery after cSCI, but its overall effects remain limited. Our main goals are to: 1) enhance rAIH/training-induced aftereffects on forelimb function and increase our understanding of the neuronal substrates in an adult rat model of chronic contusive cSCI, and 2) use this knowledge to guide the development of more effective rAIH/training approaches to improve upper limb function in humans with chronic contusive cSCI. In Specific Aim 1, using an adult rat model of chronic contusive cSCI, we will investigate the effects of rAIH frequency and dose on rAIH/training-mediated functional recovery of the impaired forelimb. Also, we will combine rAIH/training with NMDA-mediated synaptic plasticity through D-cycloserine treatment and study the effects on recovery of forelimb function. Immunocytochemistry with imaging techniques will be used to assess structural neuronal plasticity in the CST after rAIH/training. In Specific Aim 2, in people with chronic incomplete cSCI, guided by the findings in Specific Aim 1, we will study the effects of rAIH frequency and concurrent D-cycloserine treatment on rAIH/training-mediated upper limb function recovery. We will comprehensively analyze the effects of rAIH on the strength of electrophysiological and functional aftereffects in the upper limb. The proposed research will provide new knowledge on rAIH/training-mediated functional and anatomical aftereffects (Specific Aim 1), which will be used to develop effective rAIH/training protocols for people with contusive, functionally incomplete, cSCI (Specific Aim 2). The data from our experiments may lead to clinically applicable approaches that improve arm and hand function recovery after chronic contusive cSCI, which would positively impact the quality of life of our Veterans with cSCI. The relevance of this proposal is emphasized by the limited efficacy of current strategies to improve upper limb function after cSCI.